Parasite Factors: Sequestration, VAR, PfEMP1

Question 1

how can sequestration cause variations in clinical disease

Answer 1

variations in clinical disease can be caused by WHERE the parasites cause RBC sequestration - brain epithelium

Question 2

IMMUNE EVASION: how is sequestration an example of immune evasion for P. falciparum

Answer 2

prevents iRBCs from being removed by the spleen

Question 3

what are the 3 forms of sequestration?

Answer 3

• cytoadherence to endothelial cells
• to uninfected cells (rosetting)
• to platelets, causing clumping

Question 4

what is the name of the parasite receptor responsible for all forms of sequestration

Answer 4

PfEMP1

Question 5

what host receptors does PfEMP1 variants bind to to mediate sequestration

Answer 5

host: endothelial cells
- CD36, scavenger receptor clearing dying/damaged cells
- expressed on microvascular endothelial cells NOT IN THE BRAIN THO
- also on immune cells, platelets, rbc, macros/monos

ICAM-1: on WBCs and endothelial cells
- leukocyte trafficking
- upregulated in response to inflammatory cytokines like TNF

CR1 - compliment receptor 1 = rosetting

EPCR
- expressed on larger vessels
-related to blood clotting, that may go awry during malaria (anticoagulant pathway)
- soluble form in plasma
- helps maintain endothelial barrier integrity

CSA - placenta

Question 6

what is PfEMP1 and what is it encoded by

Answer 6

polymorphic family of adhesin receptors that mediated binding to host cells and immune evasion through antigenic variation

VAR genes encode antigenically distinct PfEMP1 proteins, 50-60 var genes, each gene only encodes one Pfemp1 protein

only 1 protein expressed on an iRBC membrane at a time

Question 7

PfEMP1 structure

Answer 7

PfEMP1 proteins are large, complex proteins with several domains, each contributing to their ability to bind specific host receptors.
Key structural features include:
DBL (Duffy-binding-like) domains: Mediate receptor binding, such as to EPCR or ICAM-1. SubGroups - a,b,y,delta, X
CIDR (Cysteine-rich interdomain regions): Also involved in receptor binding and cytoadherence - Subgroups, b,g,delta, PAM
Each variant has both, but the arrangement and type of domains differ between PfEMP1 variants, reflecting the diversity of the var gene family.

Question 8

how do var genes confer genetic variability among Falciparum strains?

Answer 8

every parasite has different set of 60 VAR genes, isolates rarely overlap - very diverse

switching in var gene = change in PfPR1 in daughter cells, antigenic variation

The wide variation in var genes allows the parasite to adapt to different adhesion environments to avoid splenic clearance. Additionally, multiple var genes of the same binding phenotype exist, allowing the parasite to maintain adhesion to particular receptors despite antibody recognition

Question 9

What are the 3 groups of PfEMP1 molecules and what do they mean?

Answer 9

3 groups A, B, C
A

DOES NOT BIND TO CD36, Associated with severe malaria, rosetting, brain-endo cerebral malaria.

B + C - C bind to CD36, smaller, less extracellular domains, bind to platelet, platelet-mediated clumping, associated with less severe malaria but widespread sequestration in other non-brain issues

no recombination in groups so always have a genes

Question 10

whats a domain cassette and give examples

Answer 10

particular groups of pfemp1 domains that occur together more often than would be expected by chance
- represent functional adhesion units? have particular function
DC11+DC16 - bind to red cells, rosette
DC13+DC8 bind to brain endothelial cells

DC11- red cells and IgM in serum

Question 11

what are the “special var genes”

Answer 11

conserved across isolates, in all of them

Var2- encodes Var2CSA pfemp1 variant. Bind chondroitin sulfate A, a form of which is only found in placenta
- inflammation of fibrosis, impairs function of placenta = low birth weight babies

VAR 1+3 - does other stuff idk

after 1-2 pregnancies, women develop antibodies that recognise Var2CSA variant - protection against malarian pregnancy
+ because its conserved, protected in future pregnancies from other isolates

Question 12

how are var genes being used for vax stuff

Answer 12

var2csa basis of vaccine to prevent malarian pregnancy + placental sequestration

Question 13

how do var genes/pfemp1 contribute to immune evasion and malaria survival?

Answer 13

antigenic variation
- switch expression of parasite surface antigens to avoid host antibodies

• antigenic variation, mutually exclusive expression of surface antigen to avoid host antibody response, mechanism for switching between one receptor and another, only one family member expressed at a time in a cell
• different pfEMP1 variants come to dominant in each parasitaemia wave, as host makes antibodies, leading to clearance of all those except those expressing different type, parasite switches = new wave
• prolonged infections, long term survival esp in seasonal transmission